Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial

Introduction and methods

PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) was a randomized, double-blind, active treatment–controlled, clinical trial that enrolled patients ≥18 years with heart failure (HF) and left ventricular ejection fraction (LVEF) ≤40%, NYHA class II-IV, and elevated biomarkers, or a HF-associated hospitalization within 12 months before enrollment [1].

Patients were randomized to enalapril 10mg twice daily, or sacubitril/valsartan 200mg twice daily, in a 1:1 ratio, after a run-in phase to test for intolerance. PARADIGM-HF showed that sacubitril/valsartan, compared with enalapril, significantly reduced CV mortality, HF-associated hospitalization (HFH), and all-cause mortality in patients with HF and reduced LVEF [2]. Health-related quality of life (HRQL) was also assessed, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) [3].

In this secondary analysis of the PARADIGM-HF data, individual physical and social activity items in the KCCQ domains were evaluated, in order to assess the responsiveness of each individual activity to sacubitril/valsartan. The KCCQ is a 23-item, disease-specific questionnaire, which was answered 6 times during the study and was used to assess HRQL at 8 months. Patient’s responses were scaled from 0 to 100, with 0 indicating extremely or severely limited and 100 indicating not at all limited [4].

Main results

Sacubitril/valsartan was significantly associated with a 5-point or greater improvement in score in a combined physical and social activity mean score with adjustment for baseline score at 8-month follow-up (OR: 1.12; 95%CI: 1.00-1.24; P = 0.04).

Sacubitril/valsartan was also significantly associated with an improvement of the following activities:

walking 100 yd on level ground (OR: 1.13; 95%CI: 1.03-1.24; P = 0.01)

gardening (OR: 1.17; 95%CI: 1.07-1.28; P = 0.001)

jogging (OR: 1.12; 95%CI: 1.02-1.24; P = 0.02)

hobbies (OR: 1.16; 95%CI: 1.05-1.28; P = 0.002)

household chores (OR: 1.20; 95%CI: 1.09-1.32; P < 0.001)

sexual relationships (OR: 1.18; 95%CI: 1.05-1.33; P = 0.005)

Improvement in combined physical and social activity during 8 months was associated with reduced risk of the primary composite end point of CV death or first HFH (HR: 0.79; 95%CI: 0.70-0.90).

Conclusion

In patients with heart failure and reduced ejection fraction, sacubitril/valsartan significantly improved limitations in physical and social activities compared with enalapril, with the largest response seen in household chores and sexual relationships.